Impaired inhibitory control of cortical synchronization in fragile x

24 Fragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by severe 25 cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. 26 Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory 27 neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes 28 contributes to these deficits. Here we show specific inhibitory circuit dysfunction in layer II/III 29 of somatosensory cortex of Fmr1 KOs. We demonstrate reduced activation of somatostatin 30 (SOM)-expressing low-threshold-spiking (LTS) interneurons in response to the group I 31 metabotropic glutamate receptor (mGluR) agonist DHPG in Fmr1 KOs, resulting in impaired 32 synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in 33 synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, 34 indicating a weakened LTS interneuron network in Fmr1 KOs. Together, these findings reveal a 35 functional defect in a single subtype of cortical interneuron in Fmr1 KOs. This defect is linked to 36 altered activity of the cortical network in line with the FXS phenotype. 37 38